Non-small-cell lung cancer (NSCLC) (synonym for non-small-cell carcinoma) including squamous carcinoma, adenocarcinoma and large cell carcinoma, is characterized by slower cell division than small cell carcinoma; as well as late spread and metastasis, representing about 80-85% of total lung cancer. Data shows that current morbidity of lung cancer in our country is rising 26.9% annually, with the number of patient newly-diagnosed with lung cancer increasing by 120,000 from 2000 to 2005, where the number of male patients increased from 260,000 to 330,000 and the number of female patients increased from 120,000 to 170,000. Furthermore, lung cancer has also becoming the first common one among all cancers in most regions in china. For example in Beijing, the morbidity of lung cancer increased by 56% from 2001 to 2010, during which one out of five patients newly-diagnosed with cancer is a patient affected with lung cancer. For another example in Zhejiang province, lung cancer still ranks at the top in “cancer spectrum” in 2011 issued by Zhejiang Cancer Hospital. For still another example in Guangzhou province, the morbidity of lung cancer is seven times more than that for 30 years ago.
With the progress of molecular medicine and the development of target drug, patients with advanced NSCLC have been treating with individualized therapy. At present in clinic application, the individualized therapy targeting NSCLC mainly aims at the epidermal growth factor receptor (EGFR) mutation and the Anaplastic lymphoma kinase (ALK) fusion gene, both of which have definite molecular targets, corresponding target assay technology and commercial target medicine, with clinical efficacy improved obviously.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, which is originally found in a subtype of anaplastic large cell lymphoma (ALCL) and thus is denominated as the Anaplastic Lymphoma kinase (Science, 1994, 263, 1281-1284; Oncogene, 1994, 9, 1567-1574). ALK fusion gene is a potent carcinogenic gene that is newly discovered as one of NSCLC-driven gene, with echinoderm microtubule related protein 4 (EML4-ALK) as the most common one. Abnormality in the ALK gene, such as translocation, point mutation and gene amplification, will result in abnormal kinases fused with other genes, which involve in carcinogenesis. The ALK fusion gene is generally found in non-smoking or less-smoking patients with lung adenocarcinoma. ALK-positive non-small cell lung cancer is a subtype of lung cancer newly discovered in 2007, representing 3% to 5% of total NSCLCs.
Although it has been studied a large number of compounds with inhibitory activity against protein kinases and some protein kinase inhibitors have been commercially available for NSCLC therapy, such as Crizotinib, there still remains many deficiencies, for example, drug resistance. The EML4-ALK fusion gene serving as a new target for cancer therapy has been validated with the first generation ALK inhibitor, Crizotinib (from Prizer), which was approved by FDA rapidly in November 2011 as the first one of the first-line drug for ALK-positive NSCLC therapy based on exhibition of good efficacy in clinical trials with around 60% objective response rate and about 10 months of survival without cancer progression. However, the patient under such the therapy is found to become resistant after 9 to 12 months. Currently, it is considered that the secondary resistance is at least due to self-secondary mutation of the ALK kinase, including L1196M, G1269A, S1206Y, G1202R, 1151Tins, L11152R and C1156Y, with L1196M and G1269A detected at highest frequency in clinic. It has been revealed by researchers that the secondary mutation of ALK kinase is found in about one third of Crizotinib-resistant patients and no obvious progress is observed in about 40% ALK-positive patients under continuing therapy with Crizotinib. Moreover, it is also observed from two clinical trials for Crizotinib that the most common side effects are visual impairment, nausea, diarrhea, vomiting, edema and constipation, with an occurring rate above 25%.
As the Next-Generation ALK inhibitor developed by Novartis, LDK378 still exhibits 80% response rate in 88 patients with the ALK-positive NSCLCs, who had undergone the Crizotinib therapy, in the early clinical trial, and thus was awarded as “breakthrough” by FDA in March 2013 and approved as Ceritinib (trade name: Zykadia) by FDA in April 2014 to treat patients with ALK-positive NSCLCs who had been resistant to Crizotinib based on inhibition of Crizotinib-resistant mutation by LDK378. It is revealed by research that LDK378 inhibits the Crizotinib-resistant mutation, including L1196M, G1269A, 1171T and S1206Y, with G1202R and F1174C excluded, indicating certain limitation. Besides, the clinical dosage of the Ceritinib is large, about 750 mg, P.O qday.
Therefore, all the famous pharmaceutical companies have been focusing on development of a novel safer and more effective ALK inhibitor that would bring huge social values and economic interests. A novel ALK inhibitor having improved resistance and druggability can be developed by modifying structures of candidate compound, therefore improving bioactivity and bioavailability, which is of greatly importance for diseases caused by the ALK mutation in clinic. Thus, there is still a need to improve the ALK inhibitor.